tbuckley/cabot-search huggingface dataset:
Abstract 2282: Efficient sample preparation with Covaris AFA® technology enhances confidence in Illumina® TruSight™Oncology 500 Assay
Authors: Debadeep Bhattacharyya, Kasturi Pal, Eugenio Daviso, Ulrich Thomann
Journal: Cancer Research (2022)

Abstract High throughput and robust DNA fragmentation is a critical step in Next Generation Sequencing (NGS) for clinical genomics, ultimately ensuring higher quality for the final sequencing data. The typical requirements in NGS workflow (nucleic acid fragmentation, library preparation, sequencing, etc) comprise scalability, efficiency, reliability, and robustness. Failures to achieve confidence in any of the steps can negatively impact sequence data, rendering them unusable for diagnosis. Covaris’ Adaptive Focused Acoustics® (AFA®) technology enables efficient DNA fragmentation regardless of DNA concentration and starting molecular weight, ensuring a tight fragment size distribution, minimal sample loss, and most importantly, desired reliability and reproducibility.Illumina®’s TruSight™ Oncology 500 (TSO 500) protocol describes an enrichment-based approach to convert DNA and RNA extracted from formalin-fixed paraffin embedded (FFPE) tissue samples into libraries enriched for cancer-related genes that can be sequenced on Illumina® sequencing systems. The TSO 500 assay is optimized to prepare libraries from genomic DNA (gDNA) that is sheared to optimized fragment sizes and offers high fidelity determination of DNA variants across 523 cancer relevant genes. The TSO 500 assay is the assay of choice across most cancer centers using a standardized pipeline and therefore is suitable for routine use in precision oncology as a comprehensive genomic profiling solution. This study focuses on demonstrating the optimized DNA fragmentation protocol for TSO 500 assay with parallel 8-sample processing with an ML230 Focused-ultrasonicator. Citation Format: Debadeep Bhattacharyya, Kasturi Pal, Eugenio Daviso, Ulrich Thomann. Efficient sample preparation with Covaris AFA® technology enhances confidence in Illumina® TruSight™Oncology 500 Assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2282.
Preferential uptake of SARS-CoV-2 by pericytes potentiates vascular damage and permeability in an organoid model of the microvasculature
Authors: Abdullah O Khan, Jasmeet S Reyat, Harriet Hill, Joshua H Bourne, Martina Colicchia, Maddy L Newby, Joel D Allen, Max Crispin, Esther Youd, Paul G Murray, Graham Taylor, Zania Stamataki, Alex G Richter, Adam F Cunningham, Matthew Pugh, Julie Rayes
Journal: Cardiovascular Research (2022)

Thrombotic complications and vasculopathy have been extensively associated with severe COVID-19 infection; however, the mechanisms inducing endotheliitis and the disruption of endothelial integrity in the microcirculation are poorly understood. We hypothesized that within the vessel wall, pericytes preferentially take up viral particles and mediate the subsequent loss of vascular integrity.
Abstract 2340: Evaluation of metabolic and hormonal disorders in Yemeni women with breast cancer attending national oncology center in Mukalla, Yemen
Authors: Lotfi Saeed Bin Dahman, Zaki Farag Sanoon, Waleed Khalid Kaleem, Mariam Ahmed Humam, Shaima Adeeb Bamhraz, Noor Adeeb Bamatraf, Khadija Mohmmed Humran, Fatima Lutfi Albada, Yaser Saeed Obad
Journal: Cancer Research (2022)

Abstract Background: Metabolic syndrome has been linked to many adverse health consequences, including breast cancer. This study aimed to evaluate the metabolic and hormonal disorders and assess the effect on estrogens in Yemeni women with breast cancer. Patients and Methods: A total of 69 Yemeni women with breast cancer were recruited into the cross-sectional study. This study was conducted at the National Oncology Center in Mukalla, Yemen, from15th March to 30th July 2021. Anthropometric data and blood pressure were taken from each participant. Fasting blood glucose FBG, HbA1c, lipid profile, C-reactive protein (CRP), were measured using the chemical autoanalyzer (Mindray Bs230 autoanalyzer, Mindray Diagnostics). Insulin, estradiol, and testosterone were measured using Mindray CL-960i, Mindray Diagnostics ). Data were analyzed by using SPSS. Results: The mean age of the participants was 48.17±11.0 years. The majority were normal weight(40.6%), and some were obese (30.4%) and overweight (29.0%). The majority had breast cancer stage2 (53.6%), and some were stage 4 (24.6%) and stage 3 (21.7%). Obese breast cancer women had significantly higher weight (P&amp;lt;0.001), BMI (P&amp;lt;0.001), waist (P&amp;lt;0.001), and hips (P&amp;lt;0.001) than the normal weight group. Furthermore, obese breast cancer women had significantly higher HbA1c(P=0.016), TC (P&amp;lt;0.001), and LDL-C (P=0.032) than the normal weight group. Insulin was positively associated with FBG (P=0.001) and HOMA-IR (P&amp;lt;0.001). Estradiol was positively associated with total cholesterol (P=0.004), triglycerides (P=0.007), and CRP (P=0.026). testosterone was negatively associated with CRP (P=0.011) and estradiol (P=0.019) in the combined groups studied. Conclusion: Metabolic syndrome is more prevalent in breast cancer patients and is more likely to develop breast cancer. Citation Format: Lotfi Saeed Bin Dahman, Zaki Farag Sanoon, Waleed Khalid Kaleem, Mariam Ahmed Humam, Shaima Adeeb Bamhraz, Noor Adeeb Bamatraf, Khadija Mohmmed Humran, Fatima Lutfi Albada, Yaser Saeed Obad. Evaluation of metabolic and hormonal disorders in Yemeni women with breast cancer attending national oncology center in Mukalla, Yemen [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2340.
Abstract 161: Regulation of Abl at mitotic centrosomes and survival by ILK in glioblastoma cells
Authors: Jonathan Dresselhuis, Maddisen Brown, Nicole Robinson, Jacqueline Tan, Michael E. Cox, Julia Mills
Journal: Cancer Research (2022)

Abstract Many cancer cells possess supernumerary centrosomes, having more than one centrosome at each pole during mitosis which can lead to aberrant mitotic division and cell death. To prevent this fate, cancer cells cluster their centrosomes at two poles during division to divide in a pseudobipolar manner. As the presence of supernumerary centrosomes is rare in normal cells, targeting the declustering of supernumerary centrosomes in cancer cells is a promising strategy for cancer treatment. Integrin-linked kinase (ILK) is an oncogenic protein and chemotherapeutic target shown to be found at the centrosome where it has a role in facilitating centrosome clustering. Inhibition of ILK, via an anti-ILK chemotherapeutic drug QLT-0267, has been shown to increase centrosome declustering causing mitotic arrest and cell death. However, not all cancers cells are susceptible to anti-ILK treatment alone. Therefore, we investigate a combination treatment strategy targeting ILK and another oncogenic kinase, Abelson kinase (Abl). Both ILK and Abl are involved in cancer cell survival, regulated by the same signalling pathways and share common binding partners that occur at the centrosome and are critical for mitosis. The ILK inhibitor QLT-0267 induced a significant sub-G1 peak following propidium iodide FACS analysis and an increase in MTT labelling, indicating that QLT-0267 significantly decreased survival in glioblastoma cell lines. These effects were augmented in the presence of imatinib, an Abl inhibitor. Moreover, QLT-0267 and imatinib, in combination, significantly increased mitotically arrested cells over the ILK inhibitor alone. Increased levels of cytosolic Abl have been associated with its transformative abilities. The ILK inhibitor effects on survival correlated with its ability to decrease cytosolic Abl levels and inhibited Abl’s localization to mitotic centrosomes in dividing glioblastoma cells. These effects were reversed by the proteasomal inhibitor MG132 (a drug that inhibits the degradation of Abl). Together these results indicate that combination treatment with QLT-0267 and imatinib are more effective then QLT-0267 alone at decreasing successful mitoses and survival in glioblastoma cells. Future studies will unravel the relationship between these oncogenic kinases at centrosomes and its effect on cancer cell cycle progression and survival. Citation Format: Jonathan Dresselhuis, Maddisen Brown, Nicole Robinson, Jacqueline Tan, Michael E. Cox, Julia Mills. Regulation of Abl at mitotic centrosomes and survival by ILK in glioblastoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 161.
Abstract 5028: Integration of molecular data into cancer patient database
Authors: Basil H. Chaballout, Avery T. Funkhouser, Bailey B. Blair, Jane L. Goodwin, Alexander M. Strigenz, Connie M. Arthur, Julie C. Martin, W. Jeffery Edenfield, Anna V. Blenda
Journal: Cancer Research (2022)

Abstract Background: Precision medicine holds promise of being a more effective method for treating complex diseases such as cancer. Nuanced care is needed, as the development and clinical course of cancer is multifactorial with influences from the general health status of the patient, germline and neoplastic mutations, co-morbidities, and environment including "lifestyle". To tailor an individualized treatment to the patient, such multifactorial data must be presented in an easy-to-use, easy-to-analyze fashion for providers to use effectively. Purpose: To address the need, we have built a searchable database integrating cancer-critical gene mutation status, serum galectin protein markers, serum and tumor glycomic profiles, with clinical, demographic, and lifestyle data points of individual patients. Methods: The initial data was acquired from breast, colon, and lung cancer patients’ serum and biopsy samples from the Prisma Health Cancer Institute Biorepository. The acquired data contains the status of 2,800 COSMIC cancer-critical gene mutations, individual patient profiles of five serum galectins, and serum and biopsy glycan structures from each patient’s glycomic profile. DNA from tumor cells was used to screen the regions frequently mutated in human cancer genes. Multiplex PCR using Ion AmpliSeq࣪ Cancer Hotspot panel v2 was performed by Precision Genetics. Enzyme-linked immunosorbent assay was employed to perform galectin profiling of cancer patient serum samples. Glycomic profiling of serum and biopsy samples was performed by the Emory Comprehensive Glycomic Core. In addition, healthy control values for galectin and glycomic profiles were obtained and added to the patient database for reference. The data is being stored using Microsoft SQL servers and is fed into an interactive web application using RStudio. Results: Our interactive database allows care providers to amalgamate cohorts from these groups to find correlations between different data types with the possibility of finding a "stage signature" based upon a combination of genetic mutations, galectin serum levels, glycan signatures, and patient clinical data and lifestyle choices. Conclusion: Our project provides a framework for an integrated interactive database to analyze molecular and clinical patterns across cancer stages and provides opportunities for increased diagnostic and prognostic power. Citation Format: Basil H. Chaballout, Avery T. Funkhouser, Bailey B. Blair, Jane L. Goodwin, Alexander M. Strigenz, Connie M. Arthur, Julie C. Martin, W. Jeffery Edenfield, Anna V. Blenda. Integration of molecular data into cancer patient database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5028.
Abstract 5304: A promising combination partner for paclitaxel in triple-negative breast cancer (TNBC) therapy
Authors: Youl-Nam Lee, Yun-hee Han, Won-Sam Kim, Cheol-Min Lee, Eun-Joung Moon, Hae-Jin Kim
Journal: Cancer Research (2022)

Abstract Cytotoxic chemotherapy is initially effective in patients with metastatic triple-negative breast cancer (mTNBC). However, most of the TNBC patients have high risk of recurrence after chemotherapy and metastatic tumor recurrence indicates rapid tumor proliferation and drug resistance. In TNBC cells, treatment with the chemotherapeutic drug paclitaxel (PTX) induces Transforming growth factor (TGF)-β signaling pathway. TGF-β is a master regulator of tumor angiogenesis and epithelial-mesenchymal transition (EMT), which are limiting the efficacy of cancer therapies and suppressing the anti-tumor immune response. TGF-β induces autophagy in tumor cells and autophagy is closely associated with cancer cell survival and contributing to resistance to therapies. The targeting of TGF-β pathway is possibly an effective strategy to inhibit drug resistance and increase the sensitivity of cancer treatment. Charis 1000 (C1K), which is currently under development, is a synthetic peptide that targets TGF-β1. As C1K partially inhibits TGF-β1-induced Smad2 phosphorylation in TNBC cells, there is no risk of side effects unlike small molecules or antibodies that completely inhibit the TGF-β1 signaling pathway. Combination therapies including chemotherapy are actively investigated as effective treatments for various cancers. PTX, one of frequently used drugs in combination therapies, increases phosphorylation of Smad2, a TGF- β1 downstream signaling pathway and induces autophagy in TNBC cells, but PTX in combination with C1K increases apoptosis while reducing Smad2 phosphorylation and autophagy. The combination of C1K with PTX in the mouse TNBC model showed significant tumor size reduction in comparison to the PTX alone group. In addition, the combination of C1K with PTX confirmed the increased apoptosis and decreased autophagy in the tumor tissues. Furthermore, the combination of C1K with PTX increased the survival rate of mice that was reduced due to the side effects of PTX. These data indicate that the drug resistance induced by TGF-β signaling pathway can be suppressed by C1K combination through TGF-β signaling modulation. C1K may be a promising combination partner for cancer treatment by reducing drug resistance and increasing apoptotic potential of anticancer drugs. Currently, a phase1 clinical trial of the C1K combination therapy with PTX is ongoing and the preclinical studies of the C1K combination with immune checkpoint inhibitors (ICIs) are actively investigated as well. Citation Format: Youl-Nam Lee, Yun-hee Han, Won-Sam Kim, Cheol-Min Lee, Eun-Joung Moon, Hae-Jin Kim. A promising combination partner for paclitaxel in triple-negative breast cancer (TNBC) therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5304.
Abstract 1897: Systematic methods to identify cancer vulnerabilities from genome-wide loss-of-function screens: An interactive framework for target discovery
Authors: John M. Krill-Burger, Ashir A. Borah, Brenton R. Paolella, James M. McFarland, Francisca Vazquez
Journal: Cancer Research (2022)

Abstract Over a thousand genome-scale loss-of-function screens have been performed, as part of efforts such as The Cancer Dependency Map (DepMap), to establish the landscape of genetic dependencies across a diverse set of cancer cell lines. A key challenge to using this resource for therapeutic target discovery is discerning common or tissue-related gene dependencies from those that represent true cancer-specific vulnerabilities. Although many successful cancer-specific targets have been identified by synthetic lethality with patient-prevalent driver mutations, the number of novel synthetic lethals identified as more cancer cell lines are screened has been limited compared to the total number of newly observed selective dependencies. Better understanding of how these selective dependencies are connected to molecular features of the sensitive cell lines could unlock a wealth of potential targets. As part of the DepMap project at the Broad Institute, we created a software pipeline and interactive web-tool for researchers to interrogate the compendium of CRISPR and RNAi screens and systematically rank potential targets by several key factors, most notably selectivity, disease indication, and predictability from multi-omics features (WES, RNAseq, methylation, proteomics). A strength of our framework is the ability to explore the relationships between a dependency and its top predictive features since this could provide insights into the mechanism underlying the cellular dependency and aid in generating therapeutic hypotheses. Additionally, users can perform disease-specific analyses and incorporate annotations for small molecule tractability or drug availability. We anticipate this tool will lower the barrier to systematic genome-wide target discovery using DepMap and provide insights into strategies and best practices for nominating promising targets. Citation Format: John M. Krill-Burger, Ashir A. Borah, Brenton R. Paolella, James M. McFarland, Francisca Vazquez. Systematic methods to identify cancer vulnerabilities from genome-wide loss-of-function screens: An interactive framework for target discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1897.
Abstract 613: AL009 is a multi-Siglec inhibitor engineered to bind myeloid cells that enhances innate and adaptive immunity to cancer
Authors: Sam Nalle, Helen Lam, Cheryl Barner, Hua Long, Spencer Liang, Arnon Rosenthal, Daniel Maslyar
Journal: Cancer Research (2022)

Abstract Background - Inhibitory sialic acid-binding immunoglobulin-type lectins (Siglecs) are a subset of the Siglec family of cell surface receptors that potentiate immune tolerance. A multitude of inhibitory Siglecs on myeloid cells become engaged in sialic acid-rich tumor microenvironments, suggesting that disrupting Siglec-sialic acid signaling could confer therapeutic benefit in cancer. To accomplish this, we designed AL009, an engineered Siglec-9 extracellular domain-Fc fusion molecule that acts as a sialic acid trap and a multi-Siglec inhibitor, repolarizing suppressive myeloid cells and activating an anti-cancer response. Methods - Cooperative binding of AL009 was analyzed by flow cytometry using cultured human tumor cell lines and myeloid-derived suppressor cells (MDSCs) differentiated from primary human monocytes. Monocytes, MDSCs, and macrophages differentiated from primary human monocytes were assessed for AL009 binding by flow cytometry. AL009m (AL009 with a mouse Fc) was fluorophore-labeled and intravenously injected into B6 mice to analyze biodistribution via ex vivo tissue imaging over time. Initial toxicology screening was conducted in cynomolgus monkeys in a non-terminal study. Results - AL009 displays cooperative binding with sialic acid and Fc gamma receptors on myeloid cells. When comparing binding among myeloid cell subsets, AL009 preferentially binds MDSCs. Analysis of the biodistribution of labeled AL009m in mice showed the greatest accumulation in the spleen, consistent with immune cell targeting in vivo. Further, Fc engineering of AL009 improved the pharmacodynamic profile compared to a non-engineered Fc. In cynomolgus monkeys, single doses of 80 mg/kg appeared safe and without clinically significant findings. Conclusions - The engineered structure of AL009 leads to preferential binding to an immunosuppressive subset of myeloid cells. This targeting leads to repolarization of myeloid cells and activates an innate and adaptive anti-cancer response. Pharmacologically relevant doses of AL009 appear well-tolerated in initial studies in non-human primates, supporting further development for entry into clinical studies. Citation Format: Sam Nalle, Helen Lam, Cheryl Barner, Hua Long, Spencer Liang, Arnon Rosenthal, Daniel Maslyar. AL009 is a multi-Siglec inhibitor engineered to bind myeloid cells that enhances innate and adaptive immunity to cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 613.
Abstract 5384: Cell growth of sunitinib-resistant renal cell carcinoma was inhibited by Shikonin through necroptosis induction and Akt/mTOR signaling inhibition
Authors: Eva Juengel, Sascha D. Markowitsch, Olesya Vakhrusheva, Yasminn Akele, Jovanna Kitanovic, Patricia Schupp, Kimberly S. Slade, Anita Thomas, Igor Tsaur, Rene Mager, Thomas Efferth, Axel Haferkamp
Journal: Cancer Research (2022)

Abstract Despite the establishment of new therapy options during the last decades, advanced renal cell carcinoma (RCC) remains an uncurable disease, due to evolving drug-resistance. New, more efficient treatment strategies are still in urgent demand. Shikonin (SHI) from Traditional Chinese Medicine has exhibited anti-tumor properties in several tumor entities. Thus, in the current investigation we evaluated the impact of SHI on progressive growth and metastatic behavior, not only in therapy-sensitive (parental) but also in therapy-resistant RCC cells. Parental and sunitinib-resistant RCC cells, Caki-1, 786-O, KTCTL-26, and A498, were treated with SHI. Tumor cell growth, proliferation, clonogenic capacity, cell cycle phase distribution, induction of cell death (apoptosis and necroptosis) and the expression and activity of regulating and signaling proteins were evaluated. Moreover, the adhesion and chemotactic activity of the RCC cells after exposure to SHI were investigated. SHI did not affect cell motility but led to significant inhibition of progressive tumor cell growth in both therapy-sensitive and therapy-resistant RCC cells. Thereby, SHI significantly inhibited the growth, proliferation and clone formation in parental and sunitinib-resistant RCC cells by G2/M phase arrest through down-regulation of cell cycle activating proteins, blocking cell division. Furthermore, SHI induced apoptosis and necroptosis by activating necrosome complex proteins. Concomitantly, SHI impaired the Akt/mTOR pathway, pivotal for cell survival and growth. Thus, SHI may hold promise as an additive option in treating patients with advanced and therapy-resistant RCC. Citation Format: Eva Juengel, Sascha D. Markowitsch, Olesya Vakhrusheva, Yasminn Akele, Jovanna Kitanovic, Patricia Schupp, Kimberly S. Slade, Anita Thomas, Igor Tsaur, Rene Mager, Thomas Efferth, Axel Haferkamp. Cell growth of sunitinib-resistant renal cell carcinoma was inhibited by Shikonin through necroptosis induction and Akt/mTOR signaling inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5384.